Distributed automated manufacturing of pluripotent stem cell products

Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site–decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production system details including different quality management systems and personnel. Where possible, these were pre-addressed by implementing strategies including standardisation, cell bank mycoplasma testing and specific engineering and process improvements. However, despite such measures, unexpected deviations occurred between sites including software incompatibility and machine/process errors together with uncharacteristic contaminations. Many only became apparent during process proving or during the process run. Further, parameters including growth rate and viability discrepancies could only be determined post-run, preventing ‘live’ corrective measures. The work confirms the critical nature of approaches usually taken in Good Manufacturing Practice (GMP) manufacturing settings and especially emphasises the requirement for monitoring steps to be included within the production system. Real-time process monitoring coupled with carefully structured quality systems is essential for multiple site working including clarity of decision-making roles. Additionally, an over-reliance upon post-process visual microscopic comparisons has major limitations; it is difficult for non-experts to detect deleterious culture changes and such detection is slow

Geophysical constraints on mirror matter within the Earth

We have performed a detailed investigation of geophysical constraints on the possible admixture of mirror matter inside the Earth. On the basis of the Preliminary Reference Earth Model (PREM) -- the `Standard Model' of the Earth's interior -- we have developed a method which allows one to compute changes in various quantities characterising the Earth (mass, moment of inertia, normal mode frequencies etc.)due to the presence of mirror matter. As a result we have been able to obtain for the first time the direct upper bounds on the possible concentration of the mirror matter in the Earth. In terms of the ratio of the mirror mass to the Earth mass a conservative upper bound is $3.8\times 10^{-3}$. We then analysed possible mechanisms (such as lunar and solar tidal forces, meteorite impacts and earthquakes) of exciting mirror matter oscillations around the Earth centre. Such oscillations could manifest themselves through global variations of the gravitational acceleration at the Earth's surface. We conclude that such variations are too small to be observed. Our results are valid for other types of hypothetical matter coupled to ordinary matter by gravitation only (e.g. the shadow matter of superstring theories).Comment: 25 pages, in RevTeX, to appear in Phys.Rev.

A comparison of the pharmacokinetics of Aspen Ceftriaxone and Rocephin in community-acquired meningitis

BACKGROUND. Community-acquired bacterial meningitis (CABM) is a life-threatening condition that is common among immunocompromised individuals. Intravenous ceftriaxone, of which Rocephin (ROC) is the originator brand, is recommended as first-line therapy in South Africa. Despite concerns regarding therapeutic equivalence with generic agents, this is the first study that has been conducted comparing clinical pharmacokinetics (PK) of a generic ceftriaxone formulation with the originator. OBJECTIVE. To compare the PK and safety of Aspen Ceftriaxone (AC) and ROC in the treatment of adult CABM. METHODS. A total of 63 eligible patients were randomised 1:1 to receive 2 g of either medication twice daily for a duration based on the identity of the causative organism and their physician’s clinical judgment. The primary endpoint of this study was the comparison of clinical PK, specifically the concentrations of each drug in the cerebrospinal fluid with corresponding paired plasma samples. While this study was underpowered to assess efficacy, safety could be evaluated on the basis of reported adverse events. RESULTS. The two patient groups were epidemiologically similar. There were no statistically significant differences in PK between either agent, nor any difference with regard to safety. CONCLUSION. AC can be considered as equivalent to ROC with regard to PK and safety in patients with CABM.Aspen Pharmacare Ltd, SA.http://www.samj.org.zaam2014ay201

MHD equilibrium properties of tokamak fusion reactor designs

The equilibrium properties of several Tokamak Reactor Designs are analyzed and compared for varying pressure and current profiles using the Princeton Equilibrium Code. It is found that the UWMAK configuration has a broader range of equilibria than the Princeton Reference Design configuration, but that the safety factor on axis is less than unity for peaked current distributions. The Argonne Experimental Power Reactor has a satisfactory range of equilibria, but a means of limiting or diverting the plasma has not yet been proposed, and this may substantially change the results obtained. (auth

Temporal, spatial, and structural patterns of adult trembling aspen and white spruce mortality in Quebec's boreal forest

Temporal, spatial, and structural patterns of adult trembling aspen (Populus tremuloides Michx.) and white spruce (Picea glauca (Moench) Voss) mortality were studied in intact 150-year-old stands in the southwestern boreal forest of Quebec. For both species, mortality decreases (number of dead trees/total number of trees) with distance from the lake edge until 100-150 m, from which point it slightly increases. Strong peaks in mortality were found for 40- to 60-year-old aspen mainly between 1974 and 1992. Such mortality in relatively young aspen is likely related to competition for light from the dominant canopy trees. Also, the recruitment of this young aspen cohort is presumably the result of a stand breakup that occurred when the initial aspen-dominated stand was between 90 and 110 years old. For spruce, strong peaks in mortality were found in 110- to 150-year-old trees and they occurred mainly after 1980. No clear explanation could be found for these peaks, but we suggest that they may be related to senescence or weakening of the trees following the last spruce budworm outbreak. Suppressed and codominant aspen had a much higher mortality ratio than spruce in the same height class, while more surprisingly, no difference in mortality rate was found between dominant trees of the two species. Most spruce trees were found as standing dead, which leads us to reject the hypothesis that windthrow is an important cause of mortality for spruce in our forests

Limit on Bs0B^0_s oscillation using a jet charge method

A lower limit is set on the B_{s}^{0} meson oscillation parameter \Delta m_{s} using data collected from 1991 to 1994 by the ALEPH detector. Events with a high transverse momentum lepton and a reconstructed secondary vertex are used. The high transverse momentum leptons are produced mainly by b hadron decays, and the sign of the lepton indicates the particle/antiparticle final state in decays of neutral B mesons. The initial state is determined by a jet charge technique using both sides of the event. A maximum likelihood method is used to set a lower limit of \, \Delta m_{s}. The 95\% confidence level lower limit on \Delta m_s ranges between 5.2 and 6.5(\hbar/c^{2})~ps^{-1} when the fraction of b quarks from Z^0 decays that form B_{s}^{0} mesons is varied from 8\% to 16\%. Assuming that the B_{s}^{0} fraction is 12\%, the lower limit would be \Delta m_{s} 6.1(\hbar/c^{2})~ps^{-1} at 95\% confidence level. For x_s = \Delta m_s \, \tau_{B_s}, this limit also gives x_s 8.8 using the B_{s}^{0} lifetime of \tau_{B_s} = 1.55 \pm 0.11~ps and shifting the central value of \tau_{B_s} down by 1\sigma

Measurement of the Bs0^0_s lifetime and production rate with Ds−l+^-_s l^+ combinations in Z decays

The lifetime of the \bs meson is measured in approximately 3 million hadronic Z decays accumulated using the ALEPH detector at LEP from 1991 to 1994. Seven different \ds decay modes were reconstructed and combined with an opposite sign lepton as evidence of semileptonic \bs decays. Two hundred and eight \dsl candidates satisfy selection criteria designed to ensure precise proper time reconstruction and yield a measured \bs lifetime of \mbox{\result .} Using a larger, less constrained sample of events, the product branching ratio is measured to be \mbox{\pbrresult